Gr1+ Cells Suppress T-Dependent Antibody Responses in (NZB x NZW)F1 Male Mice through Inhibition of T Follicular Helper Cells and Germinal Center Formation
Gr1+ Cells Suppress T-Dependent Antibody Responses in (NZB x NZW)F1 Male Mice through Inhibition of T Follicular Helper Cells and Germinal Center Formation
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DOI：
10.4049/jimmunol.1302479
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发表时间：
2014-02-15
影响因子：
4.4
通讯作者：
Jorgensen, Trine N.
中科院分区：
文献类型：
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作者：
Der, Evan;Dimo, Joana;Jorgensen, Trine N.
系统性红斑狼疮是一种自身免疫性疾病，其特征是自身反应性抗体的产生增加。这种疾病在妇女中的发病率比男子高得多。虽然睾酮已被证明在疾病中具有保护作用，而雌激素则会加剧疾病，但男性和女性之间患病率的差异仍然没有得到很好的理解，其背后的机制也不清楚。我们最近描述了雄性（新西兰黑[NZB] x新西兰白色[NZW]）F1小鼠具有更高水平的Gr 1（+）CD 11b（+）细胞，并且这些细胞抑制体内自身抗体的产生。在这篇文章中，我们扩展我们的研究结果表明，类似于人类，女性狼疮倾向（NZB x NZW）F1小鼠也响应与胸腺依赖性抗原免疫比男性同窝出生的更强的抗体反应。此外，Gr 1表达细胞的存在或不存在不仅控制雄性（但不控制雌性）（NZB x NZW）F1小鼠的Ag特异性Ab反应，而且还显着改变CD 4（+）T细胞的体外和体内活化和分化。特别是，我们发现来自雄性（NZB x NZW）F1小鼠的Gr 1（+）细胞抑制CXCR 5（+）PD-1（+）T滤泡辅助细胞的分化和效应功能，从而控制生发中心的形成和浆细胞分化。这一新的发现有力地支持了开发靶向髓系细胞亚群的新药的努力，这些药物用于治疗许多女性占优势的T和B细胞介导的疾病。
Systemic lupus erythematosus is an autoimmune disease characterized by elevated production of autoreactive Abs. The disease has a much higher prevalence in women than in men. Although testosterone has been shown to be protective in the disease, and estrogens exacerbating, the discrepancy in prevalence between men and women is still not well understood and the mechanism behind it is unknown. We have recently described that male (New Zealand black [NZB] x New Zealand white [NZW])F1 mice have higher levels of Gr1(+)CD11b(+) cells, and that these cells suppress autoantibody production in vivo. In this article, we extend our findings to show that similarly to humans, female lupus-prone (NZB x NZW)F1 mice also respond with stronger Ab responses to thymusdependent Ag immunization than male littermates. Furthermore, the presence or absence of Gr1-expressing cells not only control Ag-specific Ab responses in male, but not female, (NZB x NZW)F1 mice, but also significantly alter the activation and differentiation of CD4(+) T cells in vitro and in vivo. In particular, we found that Gr1(+) cells from male (NZB x NZW)F1 mice suppress the differentiation and effector function of CXCR5(+) PD-1(+) T follicular helper cells, thereby controlling germinal center formation and plasma cell differentiation. This new finding strongly supports efforts to develop new drugs that target myeloid cell subsets in a number of T and B cell-mediated diseases with a female predominance.